Tetrasubstituted dienes

Hydrolysis of zirconacyclopentadienes provides, in a stereocontrolled manner, 1,2,3,4-tetrasubstituted dienes 13. In particular, unsymmetrical diene derivatives 14 can be prepared by this method (Eq. 2.10) [14]. 

Alkene, trisub stituted Alkene, tetrasubstituted Diene... 

Hydrolysis. Hydrolysis of zirconacyclopentadienes (103) with inorganic acid see Acids Acidity) provides, in a stereocontrolled manner, 1,2,3,4-tetrasubstituted dienes. Protonolysis with weak organic acids such as ethanol gives monoprotonated dienylzirconocene, which can be reacted with electrophiles to yield pentasubstituted diene derivative (Scheme 31). In the same way, p,y unsaturated amines are obtained by cleavage of Zr-C and Zr-N bonds of azazirconacycles. 

Even the tetrasubstituted diene (117) underwent smooth cycloaddition to p-quinones, thereby opening a convenient route to polyoxygenated anthraquinone pigments, e.g. (117) + (118) - (119). ... 

Similar results have been reported for the closely related complex 91, which was an efficient catalyst for the RCM of di-, tri- and tetrasubstituted diene and enyne substrates. The reactions were performed in a homogeneous mixture of [bmim][PF6]/CH2Cl2 (1 9 v/v) as the solvent and in the presence of 1 mol.% of catalyst 91 at 45 °C (Scheme 1.54). Catalyst 91 combined the advantages of high reactivity and a high level of recyclability and reusability with only a very slight loss of activity. 

The same authors later expanded the concept and additionaly provided an imidazolium-tagged Howeyda-Grubbs ruthenium carbene catalyst for the RCM reaction [260]. The resulting system proved to be highly active for the conversion of di-, tri- and tetrasubstituted diene and enyne substrates. In the catalyst solvent system [BMIM][PF6]-CH2Cl2 (volume ratios 1 1 to 1 9) the catalyst could be recycled 17 times with only very slight loss in activity. Also in this work it was demonstrated that the imidazolium tag is essential to obtain a stable and recycleable catalyst. 

The Diels-Alder addition of the tetrasubstituted diene (126) to benzoquinone derivatives has led to a synthesis of kermesic acid (127) and related species, and the exocyclic sulphur-substituted diene (128) can be employed in the regioselec-tive construction of bicyclic systems/ ... 

A major difficulty with the Diels-Alder reaction is its sensitivity to sterical hindrance. Tri- and tetrasubstituted olefins or dienes with bulky substituents at the terminal carbons react only very slowly. Therefore bicyclic compounds with polar reactions are more suitable for such target molecules, e.g. steroids. There exist, however, several exceptions, e. g. a reaction of a tetrasubstituted alkene with a 1,1-disubstituted diene to produce a cyclohexene intermediate containing three contiguous quaternary carbon atoms (S. Danishefsky, 1979). This reaction was assisted by large polarity differences between the electron rich diene and the electron deficient ene component. 

Isolated tetrasubstituted double bonds do not react under these conditions and the saturation of trisubstituted double bonds is extremely slow, thus limiting the general utility of the method. This difference in reactivity is used to advantage for the selective deuteration of the -double bond in androsta-l,4-diene-3,17-dione (138). In homogeneous solution, saturation usually occurs from the a-side and consequently the deuterium labels are in... 

The MT0/H202/pyridine system enjoys a broad substrate scope and has become the method of choice for the epoxidation of di-, tri-, and tetrasubstituted olefins. As an added benefit, it gives high diastereoselectivities for a number of cyclic dienes (Table 12.1). 

Simple 1,3-dienes also undergo a thermal monocyclopropanation reaction with methoxy(alkyl)- and methoxy(aryl)carbene complexes of molybdenum and chromium [27]. The most complete study was carried out by Harvey and Lund and they showed that this process occurs with high levels of both regio-and diastereoselectivity. The chemical yield is significantly higher with molybdenum complexes [27a] (Scheme 7). Tri- and tetrasubstituted 1,3-dienes and 3-methylenecyclohexene (diene locked in an s-trans conformation) fail to react [28]. The monocyclopropanation of electronically neutral 1,3-dienes with non-heteroatom-stabilised carbene complexes has also been described [29]. 

Bis(diamino)alanes (R2N)2A1H were used for the hydroalumination of terminal and internal alkenes [18, 19]. TiCb and CpjTiCb are suitable catalysts for these reactions, whereas CpjZrCb exhibits low catalytic activity. The hydroaluminations are carried out in benzene or THF soluhon at elevated temperatures (60°C). Internal linear cis- and trans-alkenes are converted into n-alkylalanes via an isomerization process. Cycloalkenes give only moderate yields tri- and tetrasubstituted double bonds are inert. Hydroaluminahon of conjugated dienes like butadiene and 1,3-hexa-diene proceeds with only poor selechvity. The structure of the hydroaluminahon product of 1,5-hexadiene depends on the solvent used. While in benzene cyclization is observed, the reaction carried out in THF yields linear products (Scheme 2-10). 

When C=Se is conjugated with double or triple bonds, selenoketone can also behave as a heterodiene in the presence of the dienophiles. A-selenoacylami-dines, used as l-selena-3-aza-l,3-dienes with 1,5 equivalents of the dienophile DMAD are converted229,231 to 4H-l,3-selenazines, Scheme 28, with 10 equivalents being transformed into tetrasubstituted 4H-selenopyran derivatives (Scheme 31). 

Reactions with alkenes and nonconjugated dienes have been described in many publications (101, 103, 106-111). Various alkenes, such as cycloalkenes as well as acyclic alkenes, up to tetrasubstituted derivatives, can react with nitroalkenes (42) (110). Only one double bond is involved in the reactions of heterodienes (42) with nonconjugated dienes (111), whereas the second double bond can be used in subsequent transformations of target nitronates (35). The reactions of heterodienes (42) with inactivated alkenes require the presence of LA as catalyst. 

Trost reported the synthesis of 1,4-dienes with ruthenium catalysis through regioselective carbometallation of alkynes with alkenes.51 Di- and trisubstituted olefins can also be obtained with arylboronic acids through an intermolecular process under rhodium,30 52 55 nickel,56 and palladium catalysis.57 Recently, Larock has reported an efficient palladium-catalyzed route for the preparation of tetrasubstituted olefins.58,59... 

Dienes such as 90 can be accessed by a multi-component reaction under ruthenium catalysis involving an allene 88 and an enone (methyl vinyl ketone in this case), with cerium(m) chloride as an additive in DMF (Scheme 26).95,96 With an allene concentration of 0.25 M, yields are moderate to good. Different ruthenium catalysts and additives were tested in order to optimize this reaction. CpRu(COD)Cl 89 and CpRu(MeCN)3PF6 appeared to be more versatile ones. The mono-, di-, tri-, and tetrasubstituted allenes have been investigated with methyl vinyl... 

Trost et alJ2 also explored the compatibility of di-, tri-, and tetrasubstituted allenes with their intermolecular Alder-ene protocol. Multiple substituents present the opportunity for a mixture of products to arise from differing regio- and chemoselectivity. 1,1-Disubstituted allenes were coupled to methyl vinyl ketone with excellent chemo-selectivity only when one set of /3-hydrogens was activated by an cy-ester or amide (Equation (69)). If the /3-hydrogens were of similar acidity, a mixture of products was obtained, as in the coupling of allenol 103 with methyl vinyl ketone dienes 104 and 105 are produced in a 1.3 1 mixture (Equation (70)). 

Butynone 93 and tetrasubstituted allene 94 combine to form acetyl cyclopenta-diene 95 (Eq. 13.30) [32]. The annulation does not proceed in satisfactory yield in the case of unsubstituted trimethylsilyl allene 96 (Eq. 13.31) [32]. This is presumably due to diminished stabilization of the cationic intermediates in the case of 96, which allows competing reaction pathways to erode the yield. 

Spino and colleagues134 studied the Diels-Alder reactions of vinylallenes aiming to synthesize six-membered rings with a tetrasubstituted exocyclic double bond, which were to be employed as precursors of quassinoids. Some representative results of their investigations have been summarized in Table 5 (equation 56). Due to the presence of two different substituents at the allene terminus of 200, facial differentiation occurred, which resulted in non-equivalent amounts of geometrical isomers 201 and 202. The major isomers obtained in each case were formed by endo attack of maleic anhydride 144 at the less hindered face of the diene. 

In the above mentioned reaction, platinum oxide and palladium on barium sulfate showed no perceptible change in the rate of hydrogen uptake. On the other hand, platinum oxide was selective in the hydrogenation of cyclohexa-2,4-diene-l,2-dicarboxylic acid to 1,4,5,6-tetrahydrophthalic acid140. A similar result may be the favored reduction of a symmetrical disubstituted double bond over a more hindered trisubstituted bond. The retarding effect of additional substitution is demonstrated in the hydrogenation of a trisubstituted double bond in the presence of a tetrasubstituted double bond (equation 53)141. 

While they have proven very selective for tiisubstituted olefins, they fail to produce high selectivity or reactivity with the substrate classes of tetrasubstituted olefins, terminal olefins, and 1,3-dienes. 

For the first time, application of sequential Diels-Alder reactions to an in situ-generated 2,3-dimethylenepyrrole was shown with various dienophiles 548 to afford 2,3,6,7-tetrasubstituted carbazoles (549). This novel tandem Diels-Alder reaction leads to carbazole derivatives in two steps, starting from pyrrole 547 and 2 equivalents of a dienophile, and is followed by 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) oxidation of the intermediate octahydrocarbazole. Mechanistically, the formation of the intermediate octahydrocarbazole appears to involve two sequential [4+2] cycloadditions between the exocyclic diene generated by the thermal elimination of acetic acid and a dienophile (529) (Scheme 5.17). 

Beccalli et al. reported a synthesis of carbazomycin B (261) by a Diels-Alder cycloaddition using the 3-vinylindole 831 as diene, analogous to Pindur s synthesis of 4-deoxycarbazomycin B (619). The required 3-vinylindole, (Z)-ethyl 3-[(l-ethoxy-carbonyloxy-2-methoxy)ethenyl]-2-(ethoxy-carbonyloxy)indole-l-carboxylate (831), was synthesized starting from indol-2(3H)one (830) (620). The Diels-Alder reaction of the diene 831 with dimethyl acetylene dicarboxylate (DMAD) (535) gave the tetrasubstituted carbazole 832. Compound 832 was transformed to the acid 833 by alkaline hydrolysis. Finally, reduction of 833 with Red-Al afforded carbazomycin B (261) (621) (Scheme 5.99). 

Aldehydes tend to be more reactive toward carbonyl oxide than ketones in the recombination reaction (Scheme 9.14, step 3). As a result, tetrasubstituted alkenes generally fail to give normal ozonides604 but rather, 75 undergoes the side reactions indicated above. A new method of ozonation carried out with alkenes adsorbed on polyethylene, however, could yield ozonides of tetrasubsituted alkenes, and even diozonides of dienes could be isolated.605... 

The course of the reaction of furan and DMAD is temperature dependent (73CJC4125). The initially formed monoadduct (118) acts as a dienophile and further addition of furan can occur at the di- or tetra-substituted double bonds. In such additions to norbornene-type dienophiles the diene is subject to steric approach control and approach to the exo face is preferred. At 25 °C the tetrasubstituted double bond acts as a dienophile and the endo,exo... 

All types of olefins can serve as substrates. Suitable acyclic olefins include ethylene, terminal and internal monoenes up to and including tetrasubstituted-double bonds, and aryl-substituted olefins. With dienes (and polyenes) an additional, intramolecular reaction pathway becomes available which leads to cyclic olefins (Reaction 2). 

Various aspects of this reaction have been summarized by Kocienski.2 It is particularly useful for synthesis of disubstituted alkenes and conjugated dienes and trienes. It fails with some trisubstituted alkenes and most tetrasubstituted. alkenes because the precursors are unstable. One advantage of this route is that rra/is-alkenes are formed preferentially or exclusively. Yields are highest when the eliminated groups can adopt a /rons-coplanar arrangement. 

A regioselective, alkoxide-directed carbometallation has been reported to occur in all cases at the site distal to the tethered alkoxide to produce functionalized tetrasubstituted 1,3-dienes [(44) - (45)].57... 

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